Genes in the HLA region of chromosome 6 are known to confer susceptibility to insulin dependent diabetes mellitus (IDDM) and other autoimmune disorders, such as rheumatoid arthritis (RA) and autoimmune thyroid disease (ATD). Specific HLA-DR, DQ and DP locus polymorphisms have been associated with these conditions. However, the causes of the occurrence of more than one autoimmune disease within an individual, or their clustering in families remains unclear. Possible explanations include linkage disequilibrium among HLA susceptibility genes and/or common environmental factors that may be related to their respective etiologies. The increased prevalence of these disorders among women suggest that hormonal factors may also be involved. To investigate the interrelationships between IDDM RA and ATD, we will address two Specific Aims. Aim 1: To estimate the cumulative incidence of RA and ATD in: a) IDDM cases, b) their parents and siblings, and c) the general population of Allegheny County, PA. We hypothesize that the incidence will be highest among the IDDM cases, and lowest in the general, population. Aim 2: To conduct an analytic epidemiologic investigation of genetic/ environmental interactions and the clustering of ATD, RA and IDDM in families. a) We hypothesize that within families, individuals with IDDM, ATD and RA will share HLA haplotypes. Comparison between families will likely reveal unique class II susceptibility alleles for each disorder. b) We hypothesize that after controlling for susceptibility, relatives with IDDM, RA or ATD will have different viral antibody profiles and/or exposure to other environmental risk factors than family members without these diseases. However, common environmental factors may contribute to the occurrence of more than one autoimmune disease within individuals and among relatives. The emerging field of molecular epidemiology has significantly contributed to our knowledge of the genetic/environmental interactions for IDDM within families and across populations. By expanding our research models, and employing state-of-the-art approaches for genetic epidemiologic analyses in families, we will identify candidate HLA susceptibility genes and environmental risk factors that contribute to the occurrence of IDDM, RA and ATD in an individual and their clustering in families. Identification of potential etiologic determinants can lead to the prevention of these autoimmune disorders, which is the ultimate objective of epidemiologic research.